XB-ART-39795
Nucl Recept Signal
2009 May 12;7:e006. doi: 10.1621/nrs.07006.
Show Gene links
Show Anatomy links
Developmental expression of retinoic acid receptors (RARs).
Dollé P
.
???displayArticle.abstract???
Here, I review the developmental expression features of genes encoding the retinoic acid receptors (RARs) and the 'retinoid X' or rexinoid receptors (RXRs). The first detailed expression studies were performed in the mouse over two decades ago, following the cloning of the murine Rar genes. These studies revealed complex expression features at all stages of post-implantation development, one receptor gene (Rara) showing widespread expression, the two others (Rarb and Rarg) with highly regionalized and/or cell type-specific expression in both neural and non-neural tissues. Rxr genes also have either widespread (Rxra, Rxrb), or highly-restricted (Rxrg) expression patterns. Studies performed in zebrafish and Xenopus demonstrated expression of Rar and Rxr genes (both maternal and zygotic), at early pre-gastrulation stages. The eventual characterization of specific enzymes involved in the synthesis of retinoic acid (retinol/retinaldehyde dehydrogenases), or the triggering of its catabolism (CYP26 cytochrome P450s), all of them showing differential expression patterns, led to a clearer understanding of the phenomenons regulated by retinoic acid signaling during development. Functional studies involving targeted gene disruptions in the mouse, and additional approaches such as dominant negative receptor expression in other models, have pinpointed the specific, versus partly redundant, roles of the RARs and RXRs in many developing organ systems. These pleiotropic roles are summarized hereafter in relationship to the receptors' expression patterns.
???displayArticle.pubmedLink??? 19471585
???displayArticle.pmcLink??? PMC2686085
???displayArticle.link??? Nucl Recept Signal
Species referenced: Xenopus
Genes referenced: acta4 npat rab40b rara rarb rarg rpe tbx2 tcf3 uqcc6
???attribute.lit??? ???displayArticles.show???
Figure 1. Expression of murine Rar genes in somite-stage embryos.Adjacent histological sections (planes of section as indicated by arrows on the schemes) from two embryos at the 8 somite (A,D,G) and 14 somite (B,C,E,F,H,I) stages were hybridized with 35S-labelled riboprobes for Rara (A-C), Rarb (D-F) and Rarg (G-I). Following emulsion autoradiography, sections are viewed under dark-field illumination showing the signal grains in white. Bright-field views are shown above for histology. Abbreviations: ce, celomic cavity; fg, foregut; hb, hindbrain; he, heart; hg, hindgut; me, mesoderm (primary mesenchyme); nc, neural crest; nf, neural folds; nt, neural tube; oc, occipital somite; ph, first pharyngeal (mandibular) arch; so, somite; sp, splanchnopleure; st, stomach primordium. From (Ruberte et al., 1991). | |
Figure 2. Early expression features of murine Rarb.A,B: Whole-mount ISH of E8.5 (dorsal view) and E9.5 (profile view) embryos hybridized with a digoxigenin-labelled Rarb probe recognizing all isoforms ('Rarb total', RARβT). Arrows point to the sharp expression boundary in the post-otic hindbrain neuroepithelium (r6/7 boundary). C-E: Comparative ISH with 35S-labelled probes specific for RARβ1/3 and RARβ2/4 isoforms, on serial parasagittal sections of an E9.5 embryo. Abbreviations: ba, first branchial arch; fg, foregut; mg, midgut; ppc, peritoneal-pericardial region; r7, rhombomere 7; sc, spinal cord; st, stomach primordium; str, septum transversum; um, umbilical region. (A,B) from (Serpente et al., 2005). (C-E) from (Mollard et al., 2000). | |
Figure 3. Expression features of murine Rarg.Parasagittal sections of E9.5 (A) and E12.5 (B) embryos; transverse section of an E12.5 embryo (C); detail of the oesophagus (oe) and stomach (st) of an E14.5 fetus (D), arrow pointing to the expression boundary at the limit of the squamous stomachal epithelium. 35S-labelled probes. Other abbreviations: I,II, branchial arches; Br, brain; br, stem bronchus; fl, forelimb bud; fm, frontonasal mesenchyme; hl, hindlimb bud; ma, mandible primordium; nc, nasal precartilage; nt, neural tube; oc, otic capsule; opv, optic vesicle; pv, prevertebra; ri, rib anlage; sk, sclerotome. From (Ruberte et al., 1990). | |
Figure 4. RAR gene and protein expression in the developing brain and eye.(A-D) Comparative ISH of RARα2, RARβ1/3 and RARβ2/4 on neighboring sections of the corpus striatum (lateral ganglionic eminence) of an E13.5 fetal mouse brain. 35S-labelled probes. (E-H) Immunofluorescence detection of RARαT, RARβT and RARγT on serial sections of an E10.5 eye. Abbreviations: cc, cerebral cortex; cs, corpus striatum; L, lens; lv, lateral ventricle; ol, olfactory epithelium; PM, periocular mesenchyme; R, neural retina; RPE, retinal pigmented epithelium; sv, subventricular zone. (A-D) from (Mollard et al., 2000). (E-H) from (Mori et al., 2001). | |
Figure 5. RAR expression in the differentiating limb.Comparative ISH of RARβ1/3, RARβ2/4, RARγ1 and RARγ2 on serial sections through the extremity (footplate) of an E13.5 hindlimb. 35S-labelled probes. Abbreviations: dc, digit precartilaginous condensation; fp, footplate; id, interdigital domain; mg, midgut; mu, muscle; zp, zeugopod (tibia/fibula region). From (Mollard et al., 2000). | |
Figure 6. RAR expression in differentiating organs.(A-C) Comparative ISH of Rarb and Rarg on neighboring sections of the lung of an E14.5 mouse fetus. (D-G) Details of Rarb expression in abdominal organs at E12.5, and in the developing kidney at E14.5. 35S-labelled probes. Abbreviations: ad, adrenal gland; br, bronchus; d, diaphragm; g, gut; l, liver; m, metanephros; o, oesophagus; p, pancreas; ps, pyloric region of the stomach; t, metanephric tubules. From (Dolle et al., 1990). |
References [+] :
Abu-Abed,
The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures.
2001, Pubmed
Abu-Abed, The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures. 2001, Pubmed
Abu-Abed, Developing with lethal RA levels: genetic ablation of Rarg can restore the viability of mice lacking Cyp26a1. 2003, Pubmed
Ang, Initiation of retinoid signaling in primitive streak mouse embryos: spatiotemporal expression patterns of receptors and metabolic enzymes for ligand synthesis. 1997, Pubmed
Batourina, Vitamin A controls epithelial/mesenchymal interactions through Ret expression. 2001, Pubmed
Bloch-Zupan, Expression of nuclear retinoic acid receptors during mouse odontogenesis. 1994, Pubmed
Blumberg, Multiple retinoid-responsive receptors in a single cell: families of retinoid "X" receptors and retinoic acid receptors in the Xenopus egg. 1992, Pubmed , Xenbase
Bohnsack, Signaling hierarchy downstream of retinoic acid that independently regulates vascular remodeling and endothelial cell proliferation. 2004, Pubmed
Bowles, Retinoic acid, meiosis and germ cell fate in mammals. 2007, Pubmed
Chen, Inhibition of Tgf beta signaling by endogenous retinoic acid is essential for primary lung bud induction. 2007, Pubmed
Chiang, An essential role for retinoid receptors RARbeta and RXRgamma in long-term potentiation and depression. 1998, Pubmed
Colbert, Retinoid signaling and the generation of regional and cellular diversity in the embryonic mouse spinal cord. 1995, Pubmed
Cuervo, Programmed cell death is required for palate shelf fusion and is regulated by retinoic acid. 2002, Pubmed
Desai, Distinct roles for retinoic acid receptors alpha and beta in early lung morphogenesis. 2006, Pubmed
Dickman, Selective regulation of cardiomyocyte gene expression and cardiac morphogenesis by retinoic acid. 1996, Pubmed
Diez del Corral, Opposing FGF and retinoid pathways: a signalling switch that controls differentiation and patterning onset in the extending vertebrate body axis. 2004, Pubmed
Diez del Corral, Opposing FGF and retinoid pathways control ventral neural pattern, neuronal differentiation, and segmentation during body axis extension. 2003, Pubmed
Dollé, Differential expression of genes encoding alpha, beta and gamma retinoic acid receptors and CRABP in the developing limbs of the mouse. 1989, Pubmed
Dollé, Developmental expression of murine retinoid X receptor (RXR) genes. 1994, Pubmed
Dollé, Retinoic acid receptors and cellular retinoid binding proteins. I. A systematic study of their differential pattern of transcription during mouse organogenesis. 1990, Pubmed
Dreyer, Retinoic acid receptors and nuclear orphan receptors in the development of Xenopus laevis. 1996, Pubmed , Xenbase
Duester, Retinoic acid regulation of the somitogenesis clock. 2007, Pubmed
Dupé, A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment. 2003, Pubmed
Dupé, Key roles of retinoic acid receptors alpha and beta in the patterning of the caudal hindbrain, pharyngeal arches and otocyst in the mouse. 1999, Pubmed
Dupé, Essential roles of retinoic acid signaling in interdigital apoptosis and control of BMP-7 expression in mouse autopods. 1999, Pubmed
Dupé, In vivo functional analysis of the Hoxa-1 3' retinoic acid response element (3'RARE). 1997, Pubmed
Ellinger-Ziegelbauer, A retinoic acid receptor expressed in the early development of Xenopus laevis. 1991, Pubmed , Xenbase
Ellinger-Ziegelbauer, The pattern of retinoic acid receptor gamma (RAR gamma) expression in normal development of Xenopus laevis and after manipulation of the main body axis. 1993, Pubmed , Xenbase
Fujiwara, Expression of retinaldehyde dehydrogenase (RALDH)2 and RALDH3 but not RALDH1 in the developing anterior pituitary glands of rats. 2007, Pubmed
Ghyselinck, Contribution of retinoic acid receptor beta isoforms to the formation of the conotruncal septum of the embryonic heart. 1998, Pubmed
Glover, Retinoic acid and hindbrain patterning. 2006, Pubmed
Gruber, RXR alpha deficiency confers genetic susceptibility for aortic sac, conotruncal, atrioventricular cushion, and ventricular muscle defects in mice. 1996, Pubmed
Grummer, Postnatal rat lung retinoic acid receptor (RAR) mRNA expression and effects of dexamethasone on RAR beta mRNA. 1995, Pubmed
Grummer, Expression of retinoic acid receptor genes in fetal and newborn rat lung. 1994, Pubmed
Hale, Characterization of the retinoic acid receptor genes raraa, rarab and rarg during zebrafish development. 2006, Pubmed
Halilagic, Retinoids control anterior and dorsal properties in the developing forebrain. 2007, Pubmed
Hernandez, Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development. 2007, Pubmed
Hind, Temporal/spatial expression of retinoid binding proteins and RAR isoforms in the postnatal lung. 2002, Pubmed
Hoover, Quantitative assessment of retinoid signaling pathways in the developing eye and retina of the chicken embryo. 2001, Pubmed
Ji, Mesodermal and neuronal retinoids regulate the induction and maintenance of limb innervating spinal motor neurons. 2006, Pubmed
Kastner, Vitamin A deficiency and mutations of RXRalpha, RXRbeta and RARalpha lead to early differentiation of embryonic ventricular cardiomyocytes. 1997, Pubmed
Kelley, Retinoic acid promotes differentiation of photoreceptors in vitro. 1994, Pubmed
Koide, Active repression of RAR signaling is required for head formation. 2001, Pubmed , Xenbase
Krezel, Differential expression of retinoid receptors in the adult mouse central nervous system. 1999, Pubmed
Krezel, Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. 1998, Pubmed
Li, A retinoic acid synthesizing enzyme in ventral retina and telencephalon of the embryonic mouse. 2000, Pubmed
Lohnes, Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants. 1994, Pubmed
Lohnes, Function of retinoic acid receptor gamma in the mouse. 1993, Pubmed
Luo, Mice lacking all isoforms of retinoic acid receptor beta develop normally and are susceptible to the teratogenic effects of retinoic acid. 1995, Pubmed
Maden, Retinoids and spinal cord development. 2006, Pubmed
Maden, Retinoids in lung development and regeneration. 2004, Pubmed
Maden, Retinoic acid in alveolar development, maintenance and regeneration. 2004, Pubmed
Maden, Retinoid signalling in the development of the central nervous system. 2002, Pubmed
Malpel, Regulation of retinoic acid signaling during lung morphogenesis. 2000, Pubmed
Mark, Function of retinoic acid receptors during embryonic development. 2009, Pubmed
Martín, Dorsal pancreas agenesis in retinoic acid-deficient Raldh2 mutant mice. 2005, Pubmed
Massaro, Retinoic acid receptor-alpha regulates pulmonary alveolus formation in mice after, but not during, perinatal period. 2003, Pubmed
Massaro, Retinoic acid treatment partially rescues failed septation in rats and in mice. 2000, Pubmed
Matt, Retinoic acid-dependent eye morphogenesis is orchestrated by neural crest cells. 2005, Pubmed
McCaffery, Asymmetrical retinoic acid synthesis in the dorsoventral axis of the retina. 1992, Pubmed
Mendelsohn, Developmental analysis of the retinoic acid-inducible RAR-beta 2 promoter in transgenic animals. 1991, Pubmed
Mendelsohn, RAR beta isoforms: distinct transcriptional control by retinoic acid and specific spatial patterns of promoter activity during mouse embryonic development. 1994, Pubmed
Mendelsohn, Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. 1994, Pubmed
Mendelsohn, Stromal cells mediate retinoid-dependent functions essential for renal development. 1999, Pubmed
Merki, Epicardial retinoid X receptor alpha is required for myocardial growth and coronary artery formation. 2005, Pubmed
Mic, Retinoic acid synthesis controlled by Raldh2 is required early for limb bud initiation and then later as a proximodistal signal during apical ectodermal ridge formation. 2004, Pubmed
Mohan, Expression of retinol-binding protein messenger RNA and retinoic acid receptors in preattachment bovine embryos. 2001, Pubmed
Mohan, Expression patterns of retinoid X receptors, retinaldehyde dehydrogenase, and peroxisome proliferator activated receptor gamma in bovine preattachment embryos. 2002, Pubmed
Mollard, Tissue-specific expression of retinoic acid receptor isoform transcripts in the mouse embryo. 2000, Pubmed
Molotkov, Retinoic acid generated by Raldh2 in mesoderm is required for mouse dorsal endodermal pancreas development. 2005, Pubmed
Molotkov, Retinoic acid guides eye morphogenetic movements via paracrine signaling but is unnecessary for retinal dorsoventral patterning. 2006, Pubmed
Mori, Systematic immunolocalization of retinoid receptors in developing and adult mouse eyes. 2001, Pubmed
Naitoh, Altered expression of retinoic acid (RA) receptor mRNAs in the fetal mouse secondary palate by all-trans and 13-cis RAs: implications for RA-induced teratogenesis. 1998, Pubmed
Niederreither, Embryonic retinoic acid synthesis is essential for heart morphogenesis in the mouse. 2001, Pubmed
Niederreither, Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. 1999, Pubmed
Niederreither, Embryonic retinoic acid synthesis is required for forelimb growth and anteroposterior patterning in the mouse. 2002, Pubmed
Niederreither, Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. 1997, Pubmed
Niederreither, The regional pattern of retinoic acid synthesis by RALDH2 is essential for the development of posterior pharyngeal arches and the enteric nervous system. 2003, Pubmed
Pfeffer, Regional specificity of RAR gamma isoforms in Xenopus development. 1994, Pubmed , Xenbase
Prabhudesai, Targeted effects of retinoic acid signaling upon photoreceptor development in zebrafish. 2005, Pubmed
Raz, Retinoic acid signaling is necessary for the development of the organ of Corti. 1999, Pubmed
Reijntjes, The control of morphogen signalling: regulation of the synthesis and catabolism of retinoic acid in the developing embryo. 2005, Pubmed
Ribes, The oxidizing enzyme CYP26a1 tightly regulates the availability of retinoic acid in the gastrulating mouse embryo to ensure proper head development and vasculogenesis. 2007, Pubmed
Ribes, Early mouse caudal development relies on crosstalk between retinoic acid, Shh and Fgf signalling pathways. 2009, Pubmed
Ribes, Retinaldehyde dehydrogenase 2 (RALDH2)-mediated retinoic acid synthesis regulates early mouse embryonic forebrain development by controlling FGF and sonic hedgehog signaling. 2006, Pubmed
Romand, The retinoic acid receptors RARalpha and RARgamma are required for inner ear development. 2002, Pubmed
Romand, Spatial distributions of retinoic acid receptor gene transcripts in the prenatal mouse inner ear. 1998, Pubmed
Rossant, Expression of a retinoic acid response element-hsplacZ transgene defines specific domains of transcriptional activity during mouse embryogenesis. 1991, Pubmed
Ruberte, Specific spatial and temporal distribution of retinoic acid receptor gamma transcripts during mouse embryogenesis. 1990, Pubmed
Ruberte, Retinoic acid receptors and cellular retinoid binding proteins. II. Their differential pattern of transcription during early morphogenesis in mouse embryos. 1991, Pubmed
Ruberte, Retinoic acid receptors and cellular retinoid binding proteins. III. Their differential transcript distribution during mouse nervous system development. 1993, Pubmed
Sakai, The retinoic acid-inactivating enzyme CYP26 is essential for establishing an uneven distribution of retinoic acid along the anterio-posterior axis within the mouse embryo. 2001, Pubmed
Schneider, Local retinoid signaling coordinates forebrain and facial morphogenesis by maintaining FGF8 and SHH. 2001, Pubmed
Serpente, Direct crossregulation between retinoic acid receptor {beta} and Hox genes during hindbrain segmentation. 2005, Pubmed
Shiotsugu, Multiple points of interaction between retinoic acid and FGF signaling during embryonic axis formation. 2004, Pubmed , Xenbase
Smith, Retinoic acid receptor isoform beta 2 is an early marker for alimentary tract and central nervous system positional specification in the chicken. 1994, Pubmed
Smith, Temporal and regional differences in the expression pattern of distinct retinoic acid receptor-beta transcripts in the chick embryo. 1991, Pubmed
Stinchcombe, Retinoic acid induced alveolar regeneration: critical differences in strain sensitivity. 2008, Pubmed
Studer, Genetic interactions between Hoxa1 and Hoxb1 reveal new roles in regulation of early hindbrain patterning. 1998, Pubmed
Tallafuss, Characterization of retinoid-X receptor genes rxra, rxrba, rxrbb and rxrg during zebrafish development. 2006, Pubmed
Thaller, Identification and spatial distribution of retinoids in the developing chick limb bud. , Pubmed
Tickle, Making digit patterns in the vertebrate limb. 2006, Pubmed
Uehara, CYP26A1 and CYP26C1 cooperatively regulate anterior-posterior patterning of the developing brain and the production of migratory cranial neural crest cells in the mouse. 2007, Pubmed
Ulven, Identification of endogenous retinoids, enzymes, binding proteins, and receptors during early postimplantation development in mouse: important role of retinal dehydrogenase type 2 in synthesis of all-trans-retinoic acid. 2000, Pubmed
Vermot, Retinaldehyde dehydrogenase 2 and Hoxc8 are required in the murine brachial spinal cord for the specification of Lim1+ motoneurons and the correct distribution of Islet1+ motoneurons. 2005, Pubmed
Vermot, Retinoic acid controls the bilateral symmetry of somite formation in the mouse embryo. 2005, Pubmed
Vermot, Retinoic acid coordinates somitogenesis and left-right patterning in vertebrate embryos. 2005, Pubmed
Vernet, Retinoic acid metabolism and signaling pathways in the adult and developing mouse testis. 2006, Pubmed
Wagner, Retinoic acid in the formation of the dorsoventral retina and its central projections. 2000, Pubmed
Wang, Retinoic acid regulates morphogenesis and patterning of posterior foregut derivatives. 2006, Pubmed
Waxman, Comparison of the expression patterns of newly identified zebrafish retinoic acid and retinoid X receptors. 2007, Pubmed
Wendling, Retinoid signaling is essential for patterning the endoderm of the third and fourth pharyngeal arches. 2000, Pubmed
Wietrzych, Working memory deficits in retinoid X receptor gamma-deficient mice. 2005, Pubmed
Wilson, The mechanisms of dorsoventral patterning in the vertebrate neural tube. 2005, Pubmed
Wongtrakool, Down-regulation of retinoic acid receptor alpha signaling is required for sacculation and type I cell formation in the developing lung. 2003, Pubmed
Zetterström, Role of retinoids in the CNS: differential expression of retinoid binding proteins and receptors and evidence for presence of retinoic acid. 1999, Pubmed
Zile, Retinoid signaling is required to complete the vertebrate cardiac left/right asymmetry pathway. 2000, Pubmed